The continued high evidence of deaths coincident with gram-negative bacterial infections underscores the importance of establishing the mechanism of acquired resistance to gram-negative bacterial endotoxins. The rationale for the research objective is based on the concept that the toxic moiety of endotoxins, Lipid A, has a common toxophore group which is also an antigenic determinant. Antibodies specific for this determinant act as opsonins and assist a normal functioning reticuloendothelial system (RES) to destroy the toxin. Lipid A complexed to bovine serum albumin (BSA) can induce pyrogenic and lethal resistance to lipopolysaccharides from the homologous organism, and many other organisms from other genera and species. The objective is to isolate and characterize the anti-Lipid A antibody from serum of rabbits immunized with Lipid BSA. Affinity chromotography using covalently linked Lipid A to acrylamide and agarose beads will be used to isolate the antibody. Biological substitution of fatty acids into the Lipid A molecule and a study of the fatty acids in Lipid A's isolated from more distantly related gram-negative bacteria may help to understand the nature of the toxophore group and its antigenic determinant within the Lipid A molecule. The role of hypersensitivity as a secondary toxicity in endotoxin pyrogenicity and lethality is under study using animals made hypersensitive, delayed and immediate, to the carrier BSA in the Lipid A-BSA complex. After establishing the immunological basis for endotoxin resistance, the ultimate goal is to modify the Lipid A molecule in such a way as to reduce its toxicity but retain its antigenicity. Such preparation may be of value as an immunizing agent used to protect the host against fatal endotoxin shock.